Interleukin 15 (IL-15), also known as MGC9721, is a 14 to 15 kDa pro-inflammatory cytokine which is expressed in multiple tissues (placenta, skeletal muscle, kidney, lung, heart, monocytes/macrophages) and numerous cell types including monocytes and macrophages, blood derived dendritic cells, epithelial and fibroblast cells, through various stimulatory conditions (Fenhiger and Caligiuri, 2001, Blood, 97(1):14-32). Interleukin-15 regulates T and natural killer (NK) cell activation, survival and proliferation. This cytokine and interleukin 2 (IL-2) share many biological activities, consistent with their shared receptor signaling components (IL-2/15Rβ and IL-2/15Rγc). However, specificity for IL-15 versus IL-2 is provided by unique private α-chain receptor that completes the IL-15Rαβγ heterotrimeric high-affinity receptor complex and thereby allows differential responsiveness depending on the ligand and high-affinity receptor expressed (Fenhiger and Caligiuri, 2001, supra). In addition, while soluble IL-15 is capable of directly stimulating cells expressing either the IL-15Rαβγ high-affinity receptor or the lower affinity IL-15Rβγ receptor, a phenomenon described as IL-15 cis presentation, it was suggested that IL-15 bound to IL-15Rα for example at the surface of one cell type could associate with and stimulate through the IL-15Rβγ expressed at the surface of another cell, a phenomenon described as IL-15 trans presentation (Stonier et al, 2010, Immunol. Lett., 127:85-92). Since in the circulation IL-15 may also be preferentially associated with soluble IL-15Rα, this trans presentation mechanism is unlikely restricted to cell-cell interactions (Bergamaschi et al, 2012, Blood 120:e1-e8).
A deleterious role for a dysregulation of IL-15 expression has been suggested in several disorders including autoimmune diseases such as rheumatoid arthritis, psoriasis and celiac disease, as well as in malignancies such as T cell leukemias. In particular, IL-15 triggers an anti-apoptotic pathway in human intraepithelial lymphocytes that is believed to be a potential new target in celiac disease-associated inflammation and lymphomagenesis (Malamut et. al., 2010, J. Clin. Invest., 120(6):2131-43). Further, it has been found that IL-15 expression is increased in human eosinophilic esophagitis and mediates similar/related pathogenesis in mice (Zhu et al., 2010, Gastroenterology, 139(1):182-93). In addition, it has been found that in the observed increased proinflammatory activity in patients with Alzheimer's disease and frontotemporal dementia, IL-15 can be used as a marker since its levels are elevated in cerebrospinal fluid of those patients (Rentzos et al., 2006, J. Geriatr. Psychiatry Neurol., 19(2):114-7).
IL-15 has also been found to play a role of central importance in activating innate immune cells, in particular NK and T cells in transplant rejection response, in particular in the case of allograft transplants (Ferrari-Lacraz et al., 2011, J Immunol., 167(6): 3478-3485).
IL-15 is also believed to be a myokine, playing various roles in muscle and fat metabolism (Raschke and Eckel, 2013, Mediators Inflamm., 320724). Excess of pro-inflammatory cytokines including IL-15 has been linked to wasting, hypermetabolic syndromes observed during trauma, injury, and cachexia associated with cancer (Martinez-Hernandez et al., 2012, Oncol Rep., 28(4):1443-52).
While it is generally considered to have anti-tumor activities through stimulation of the immune system, IL-15 has also been suggested to play detrimental roles in certain forms of cancers such as acute lymphoid leukemia and large granular lymphocytic leukemia, in addition to its abovementioned role in celiac disease-associated lymphomagenesis (Cario et al., 2007, J Clin Oncol. 25(30):4813-20).
Therefore, it would be beneficial to provide potent and specific antibodies that could bind IL-15 and neutralize its biological activities for therapeutic applications, in particular for the treatment of IL-15 related disorders, notably auto-immune and inflammatory disorders.
A fully human monoclonal anti-IL-15 antibody (146B7) has been disclosed (Villadsen et al., 2003, J. Clin. Invest., 112: 1571-1580) as not competing with IL-15 for binding its IL-15Rα receptor but potently interfering with the assembly of the IL-15 receptor α, β, γ complex. In a human psoriasis xenograft model, antibody 146B7 reduced the severity of psoriasis. In a phase I-II dose-escalation trial with antibody 146B7 (also known as AMG 714) in patients with active rheumatoid arthritis, improvements in disease activity have been observed (Baslund et al, 2005, Arthritis & Rheumatism, 52(9): 2686-2692). However, this program was discontinued for lack of efficacy (Fulmer 2009, T. SciBX 2(36)).
A monoclonal mouse anti-IL-15 antibody (B-E29) has been disclosed as preventing IL-15 binding to IL-15Rα (Bernard et al., 2004, J. Biol. Chem., 279(23): 24313-34322). A fully human anti-IL-15 antibody (DISC0280) has been disclosed as preventing IL-15 binding to IL-15Rα even more potently and efficiently than B-E29 when directly compared (Finch et al., 2011, Brit. J. Pharmacol., 162:480-490). While DISC0280 was very potent and efficient at neutralizing IL-15 activity in vitro, it failed to do so in vivo. It was therefore hypothesized that preventing binding of IL-15 to IL-15Rα could be detrimental for in vivo IL-15 neutralizing activity.
Despite the existence of anti-IL-15 antibodies in the prior art, there remains a need for developing alternative anti-IL-15 antibodies which exhibit advantageous properties in comparison to the antibodies of the prior art and/or are more efficiently and/or more easily produced.
The present invention fulfills this need by providing novel humanized antibodies specific for IL-15 deriving from mouse B-E29 antibody which do not prevent binding of IL-15 to IL-15Rα, can neutralize IL-15 in vivo and are more potent and efficient at binding and neutralizing IL-15 than the 146B7 antibody.